Pesticide Petition to Establish Tolerances for Cyantraniliprole

I . E.I. du Pont de Nemours and Company
PP No. ( 4F8258 )
EPA has received a pesticide petition (PP No. 4F8258 ) from E.I. du Pont de Nemours & Company (“DuPont”) , 1007 Market Street, Wilmington, DE 19898
, proposing pursuant to section 408 (d) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 346a (d), to amend 40 CFR part 180 .672 to establish tolerances for residues of cyantraniliprole, 3

- bromo

- 1

- (3

- chloro

- 2

- pyridinyl)

- N

- [4

- cyano

- 2

- methyl

- 6

- [(methylami no)carbonyl]phenyl]

- 1 H

- pyrazole

- 5

- carboxamide , including its metabolites and degradates, in or on the following commodities: artichokes, globe (import tolerance) at 0.1ppm; berries, low growing, except strawberries (crop subgroup 13

- 07H , import tolerance ) at 0.08 ppm; coffee, bean, green (import tolerance) at 0.05 ppm; grapes (import tolerance) at 1.5 ppm; olives (import tolerance) at 1.5 ppm; peanuts at 0.01 ppm; peanut hay at 3 ppm; pomegranates (import tolerance) at 0.01 ppm; rice, grain (import tolerance) at 0.03 pp m; soybeans, seed at 0.4 ppm; strawberries at 1.0 ppm; vegetables, foliage of legume (crop group 7) at 50 ppm; vegetables, leaves of root and tuber (crop group 2) at 40 ppm; vegetables, legume, dried shelled, except soybean (crop subgroup 6C) at 0.9 ppm; v egetables, legume, edible podded (crop subgroup 6A) at 2 ppm; vegetables, legume, succulent shelled (crop subgroup 6B) at 0.2 ppm; vegetables, root, except sugar beet (crop subgroup 1B) at 0.4 ppm; te a, dried (import tolerance) at 3 0 ppm.

EPA has determi ned that the petition contains data or information regarding the elements set forth in section 408 (d) (2) of the FFDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the pe tition. Additional data may be needed before EPA rules on the petition.
A. Residue Chemistry

1. Plant metabolism

. The metabolism of cyantraniliprole is adequately understood to support the proposed tolerances. Studies in lettuce, rice, tomato, and cotton when treated at proposed label rates showed no significant metabolites. The metabolism of cyantraniliprole in plants was similar regardless of the crop or the treatment regime. Cyantraniliprole was the principal residue in most crop fractions at various sampling points up to crop maturity. The overall metabolism of cyantraniliprole in rotated crops (wheat, red beets, lettuce, and soybeans) was consistent with metabolism seen in the primary crops.

2. Livestock Metabolism

. The metabolism of cyantraniliprole in ruminants and poultry is adequately understood to support the proposed tolerances. Lactating goat and laying hen metabolism studies were conducted. The metabolism of cyantraniliprole in the rat was consistent with that of the lactating goat (ruminant) and laying hen.

3. Analytical method

. Adequate analytical methodology, high

- pressure liquid chromatography with ESI

MS/MS detection, is available for enforcement purposes.

4. Magnitude of r esidues

. Field t rials were conducted on artichokes, low growing berries (13

- 07H0, coffee, grapes, olives, peanuts, pomegranates, rice, soybeans, legume and root vegetables, and tea with formulations containing cyantraniliprole. The trials covered a wide range of locations, climates, and soil types globally and the data obtained reflect the commercial use of the cyantraniliprole

- containing products in the major crop growing regions.
The results of the field trials substantiate cyantraniliprole as the majo r residue in harvested raw agricultural commodities.Pesticide Petition to Establish Tolerances for Cyantraniliprole

B. Toxicological Profile
1. Acute toxicity. Based on EPA criteria, technical cyantraniliprole is classified as acute toxicology category IV based on overall results from several studies. This compound is considered acute toxicology category IV for acute oral, dermal and inhalation toxicity and eye and skin irritation. Technical cyantraniliprole is not a dermal sensitizer.
No evidence of neurotoxicity was observed in studies conducted with cyantraniliprole in rats. The NOAEL in an acute neurotoxicity study was 2000 mg/kg bw and was the highest dose administered in the study.
2. Genotoxicty. Cyantraniliprole was evaluated in a battery of in vitro and in vivo genetic toxicology studies. Negative results were obtained in all studies indicating that cyantraniliprole does not cause genetic damage and, therefore, does not pose a mutagenic hazard.

3. Reproductive and developmental toxicity

. Based on the results of a two

- generation reproduction study in rats and a developmental toxicity studies in rats and rabbits, cyantraniliprole does not pose a specific concern for effects on reproduction or development.

4. Subchron ic toxicity. The primary toxicological findings in short

- term, repeated

- dose feeding toxicity studies included non

- adverse increases in liver weight in rats, mice, and dogs due to a pharmacological response to liver metabolism, an effect on thyroid hormones and associated thyroid gland histopathology in rats, a non

- adverse increase in the degree of lipid in adrenal cortical cells in both rats and mice, and changes in body weight, nutritional parameters, clinical pathology and liver histopathology in dogs.
Dermal application of cyantraniliprole to rats for 28 days did not result in any treatment related findings up to and including a maximum dose of 1000 mg/kg bw/day.
Cy antraniloprole showed no evidence of immunotoxicity in 28

- day feeding studies in rats or mice and no evidence of neurotoxicity in a 90

- day feeding study in rats.
No treatment related clinical signs indicative of potential neurotoxicity were observed in short

- term and long

- term exposure studies in rats, mi ce, or dogs.

5. Chronic toxicity

. Based on the results of chronic feeding studies in rats and mice, cyantraniliprole is not a carcinogen. The lowest NOAEL following chronic, long

- term feeding is 5.7 mg/kg/day is based on liver enzyme changes, liver histopathology and arteritis in the one

- dog study.
No treatment related clinical signs indicative of potential neurotoxicity were observed in long

- term exposure studies in rats, mice, or dogs.

6. Rat metabolism

. The absorption of 14 C

- cyantraniliprole in rats was rapid with peak concentrations occurring at 1

- 2.5 hours after low or high (10 or 150 mg/kg bw) dose administration. Tissue distribution of the absorbed dose was extensive and indicated low potential for accumulation. Excretion was substantially complete by 24

- 48 hours after dosing.
Following 14 days of dose administration the 14 C residues were readily eliminated from the plasma and tissues and confirmed minimal potential for accumulation. The profile of metabolites in urine and faeces indicated extensive metabolism consistent with that observed for the single dose study.Pesticide Petition to Establish Tolerances for Cyantraniliprole

7. Meta bolite toxicology

. Cyantraniliprole is considered to be the only molecule of toxicological relevance. Toxicology studies conducted with metabolites support this conclusion.

8. Endocrine disruption

. No relevant effects were observed on any endocrine tissue in short

- and long

- term studies in rats, mice and dogs to suggest an adverse impact on estrogen or androgen pathways or on steroid biosynthesis. Effects on thyroid hormone homeostatis were observed in rats following dietary exposure and demonstrated to be due to increased clearance of thyroid hormone as a result of enzyme induction.
C. Aggregate Exposure
The residue of concern is parent cyantraniliprole only.
No acute dietary risk assessment was needed since there is no acute tox endpoint.

The chronic reference dose (c RfD ) of 0.01 mg/kg bw/day is based on a NOAEL of 1 mg/kg bw/day from the 1

- year oral study in dogs and an uncertainty factor of 100.

1

. Dietary exposure i. Food

. Chronic dietary exposure resulting from the currently approved uses and proposed uses of cyantraniliprole is within acceptable limits for all sectors of the population. The chronic module of the Dietary Exposure Evaluation Model with Foo d Commodity Intake Database (DEEM

- FCIDTM, version 3.16) was used to conduct the assessment. This model incorporates nationwide food consumption data as reported by respondents in the 2

- day food consumption survey (2003

- 2008) of the National Health and Nutr ition Examination Survey (NHANES). The chronic exposure analysis used overall mean field trial values, processing factors, and a conservative assumption of 100% crop treated. Secondary residues in milk and meat were also included in the analysis. The resul tant exposure was within required limits (< 100% cRfD).

ii. Drinking water

. The impact of cyantraniliprole in drinking water on chronic dietary exposure was assessed. The highest modeled cyantraniliprole residue value from FIRST Tier 1 surface water and SCI GROW Tier 1 groundwater models under worst

- case conditions for chronic exposure was determined to be in surface water; when this conservative value for drinking water was included with the food residues in the chronic exposure assessment the resultant exposure was within required limits (< 100% cRfD)

.
2. Non

- dietary exposure

. Residential exposure (non

- occupational, non

- dietary exposure to consumers) was conservatively assessed for dermal post

- application exposure (children and adults), and for children the oral exposures via hand

- to

- mouth, object

- to

- mouth, and incidental ingestion of soil were also assessed. The margins of exposure (MOE) greatly exceed the 100

- fold MOE required for these routes and from the combined children’s incidental oral ingestion . Therefore, residential non

- dietary exposure is not a concern.
D. Cumulative Effects
A determination has not been made that cyantraniliprole has a common mechanism of toxicity with other substances. Cyantraniliprole does not appear to produce a common toxic metabolite with other substances. A cumulative risk assessment was, therefore, not performed for this analysis.
E. Safety DeterminationPesticide Petition to Establish Tolerances for Cyantraniliprole

1. U.S. population . Based on risk assessments performed using worst

- case exposure assumptions there is a reasonable certainty that no harm will result to the general population from the aggregate exposure to cyantraniliprole . No additional safety factors are warranted.

2. Infants and children

. Based on the risk assessments performed using worst

- case exposure assumptions there is a reasonable certainty that no harm will result to the infants and children from the aggregate exposure to cyantraniliprole . No additional safety factors are warranted.

F. INTERNATIONAL TOLERANCES
A number of international tolerances (or Maximum Residue Levels, MRL's) have been established for cyantraniliprole

.